Method of preparing pterins



Patented June 7, 1 949 2,472,481

"AUNITED STATES PA E T OF Martin E. Hultquist and Doris R. Seeger, Bound Brook, N. J., assignors to..Ameri can Cyanamid Company, New York, N. Y., a corporation of Maine H No Drawing. Application May 29, 1947,

Serial No. 751,464 Y 6 Claims. (01. 2604-;51). j

The present invention relates to a new method those formed. by. reaction of para-aminobenzoic of preparing substituted pterins. More particuacid and an amino .acid,..as the final products larly, it relates to the preparation of substituted possess the most \useful biological properties G-methyl amino pterins. when this is so. The preferred amino acid amide The process of the present invention comprises 5 is thatof glutamic acid. although other amino reacting 2,4,5-triamino-6-hydroxypyrimidine, an acidamides suchasthose of glycine, aspartic amide of para-aminobenzoic acid and a halogenacid, alanine, isovaline, cysteine and the like ated 1-chloro-3-acetoxyacetone. The general rewith para-aminobenzoic acid may be used. The action may be illustrated by the following equasalts and esters of these amino acid amides may tion: 10 also be used in the process.

in which X is a member of the group consisting In; carrying out the reaction of the present inof hydrogen and halogen, one of which is halogen, vention, the hydrogen ion concentration may Hal is halogen and R is a substituted amino radivaryfrom. a pH of lpr even less, up to about pH 7. Best results are obtained within the range The compound 2,4,5-triamino 6 hydroxypypH 1 to pH 5. rimidine is known. Although it most probably The temperature used in carrying out the reexists in the form illustrated, it may also exist action may vary from about 0 0. up to about in whole, or in part, in one or more tautomeric 60 C. or resonant forms, such as, for example, 2,4,5- The reactants can be added to each other in triamino-pyrimidone-S. As would be expected, various orders, however, it is preferred that the these tautomeric forms react similarly and refthree principal reactants are mixed together at erence hereinafter to the one tautomer includes 35 the same time. This latter method tends to-minithe like use of any of the various tautomers. The mize side reactions between two of the reactants compound is usually used in the form of one of which may result in products not forming a part its salts, such as the sulfate or hydrochloride but, of the desired compound. if desired, the free base may also be used. The compound pteroylglutamic acid has re- Substituted acyloxy acetones are in general cently been found useful in the treatment of known compounds. The preparation of l-chlorosprue, macrocytic anemias and related diseases 3-acetoxy acetone is described by Hess and Fink, of the blood. Berichte, 48, 2004 (1915). Although the equa- The process will now be illustrated in greater tion shows the use of substituted acetoxy acetone, detail in the following example. The process, it will be understood that other substituted acehowever, is by no means limited to the particular tones may be used such as propionoxy acetones, conditions of these examples. All parts are by butyroxy acetones and the like. Also, various weight unless otherwise indicated.

halogenated acetoxy acetones such as 1,1-di- Exam Z chloro-S-acetoxyacetone; 1,3-dichloro-3-acetoxyp e acetone; 1,1-dibromo-3-acetoxyacetone; 1,3-di- To 13.6 parts of l-chloro-B-acetoxyacetone disbromo 3 acetoxyacetone; 1-chloro-1-bromo-3- solved in 26 parts of glacial acetic acid is added acetoxyacetone; 1-bromo-3-chloro-3-acetoxyacea solution of 14.5 parts of bromine in 10.5 parts tone, and the like can be used. of glacial acetic acid. The bromine solution is The carbonyl radical, with its substituent R, added during an hour with simultaneous irradiarepresents an amide. The amides preferred are tion by an ultra violet lamp after which the re- 3 action mixture is stirred for another hour without the lamp.

To 12 parts of para-aminobenzoylglutamic acid and 21.1 parts of 2,4,5-triamino-6-hydroxypyrimidine sulfate is added 635 parts of water and sodium hydroxide suflicient to give the mixture a pH of 3. Afteradjusting the temperature to'40 0., the brominated solution of 1 chlro-3-acetoxyacetone is added during 15 minutes with enough sodium hydroxide to maintain the pH at 3. The mixture is then stirred for an additional 15 minutes at 40 C. and at a pH of 3 and is then allowed to stand overnight at room temperature before filtering. The dried crude pteroylglutamic acid (20.4 parts) shows an analysis of 16.6% by chemical assay and 7.29% by bioassay on S. faecalz's R and 12.2% by bioassay on L. casez'.

This product can be used as an adjunct to animal feed. Should a product of higher purity be desired, for use as a therapeutic agent for humans, then the product can be further purified by the method described in the copending application of .Brian L. Hutchings, Serial No. 669,099, filed May '11, 1946, now Patent No. 2,457,375.

We claim:

1. YA method which comprises reacting together 2,4,5-triamino-6-hydroxypyrimidine, an amide of para-aminobenzoic acid and a compound having theformula:

H H Hal-C o-c-o-c-cm i t l 0 in which X is a member of the group consisting of hydrogen and halogen, one of which is halogen, whereby compounds having the general formula,

N 6/ TOHzNHOCOR in which X is a member of the group consisting of hydrogen and halogen, one of which is halogen, whereby compounds having the general formula,

j-CHzNHOC 0R N/ amino radical, are

H H HalC-C-C-O-CCH i ii i l in which .X is a memberof the group consisting of hydrogen and halogen, one of which is halogen, whereby pteroylglutamic acid is produced and recovered.

4. A method which comprises reacting together 2,4,5-triamino 6 hydroxypyrimidine, paraaminobenzoyl glutamic acid and .l-chloro, 1- bromo-3-acetoxyacetone whereby pteroylglutamic acid is produced and recovered.

5. A method which comprises reacting together 2,4,5-triamino 6 hydroxypyrimidine, paraaminobenzoyl glutamic acid and 1,1-dibromo-3- acetoxyacetone whereby :pteroylglutamic acid is produced and recovered.

6. A method which comprises reacting together 2,4,5-triamino 6 hydroxypyrimidine, paraaminobenzoyl glutamic acid and l-chloro, 1,3-dibromo-3-acetoxyacetone whereby pteroylglutamic acid is produced and recovered.

MARTIN E. HULTQUIS'I. DORIS R. SEEGER.

No references cited. 

